Abstract
Oncolytic herpes simplex virus type 1 (oHSV-1) therapy is an emerging treatment modality that selectively destroys cancer. Here we report use of a glioma specific HSV-1 amplicon virus (SU4-124 HSV-1) to selectively target tumour cells. To achieve transcriptional regulation of the SU4-124 HSV-1 virus, the promoter for the essential HSV-1 gene ICP4 was replaced with a tumour specific survivin promoter. Translational regulation was achieved by incorporating 5 copies of microRNA 124 target sequences into the 3′UTR of the ICP4 gene. Additionally, a 5′UTR of rat fibroblast growth factor -2 was added in front of the viral ICP4 gene open reading frame. Our results confirmed enhanced expression of survivin and eIF4E in different glioma cells and increased micro-RNA124 expression in normal human and mouse brain tissue. SU4-124 HSV-1 had an increased ICP4 expression and virus replication in different glioma cells compared to normal neuronal cells. SU4-124 HSV-1 exerted a strong antitumour effect against a panel of glioma cell lines. Intracranial injection of SU4-124 HSV-1 did not reveal any sign of toxicity on day 15 after the injection. Moreover, a significantly enhanced antitumour effect with the intratumourally injected SU4-124 HSV-1 virus was demonstrated in mice bearing human glioma U87 tumours, whereas viral DNA was almost undetectable in normal organs. Our study indicates that incorporation of multiple cancer-specific regulators in an HSV-1 system significantly enhances both cancer specificity and oncolytic activity.
Highlights
Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumour [1,2,3]
Survivin and eIF4E are overexpressed in glioma cells, but downregulated in normal neuronal cells
A survivin luciferase reporter assay in rat neurons and various glioma cells confirmed overexpression of the gene in glioma cells (Figure 2A)
Summary
Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumour [1,2,3]. With the best possible treatment, GBM patients survive for only 12 to 15 months [2]. The current treatment for GBM is limited to surgical resection of the tumour, followed by radiation and chemotherapy [3]. Oncolytic virus (OV) therapy has recently emerged as a promising antitumour therapeutic mainly because its tumour specificity can selectively replicate in tumour cells while sparing normal cells [4]. Among the different oncolytic viruses, oncolytic herpes simplex virus type 1 (oHSV-1) has emerged as one of the most promising OV candidates due to its wellknown pathology in humans, extensively researched virology, well-characterized viral genome and its 150kb genome allowing ample space to integrate different transgenes and permitting of specific antiviral therapy as a safety measure [5, 6]. The efficacy and safety of oHSV-1 has been widely investigated and tested in preclinical and clinical glioma models [5]
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